Tricyclic intermediates

The alkaloid vasicine was first isolated from Adhatoda vasica in 1925 but the structure (996) was elucidated only after a great amount of work, culminating in two independent syntheses in 1935 (B-53MI21301). It was made subsequently by a simple route from 2-aminobenzaldehyde and 4-amino-2-hydroxybutyraldehyde (994) followed by dehydration of the tricyclic intermediate (995) (60TL(25)44>. Vasicine has bronchodilatory activity of a low order. Two related unnamed alkaloids (997) and (998) were obtained in 1965 from members of the Araliaceae family, viz. Mackinlaya subulata and M. macrosciadia both had been synthesized earlier (66AJC151). 

The pentacyclic plant alkaloid camptothecin has been a popular synthetic target because of its antitumor activity. Retrosynthetic disconnection to tricyclic intermediate A and chiral lactone B followed from multistrategic planning. 

A second route to the key tricyclic intermediate A for the synthesis of gibberellic acid was also developed (Ref. 8) ... 

The synthesis of the tricyclic intermediate A was further improved by the development of a short and stereocontrolled synthesis of compound B (Ref. 9) ... 

Cava and Schlessinger have reported the synthesis of 1,2,3-triphenyl-isoindole (65) in 78% yield from 1,3-diphenylisobenzofuran (68) hy reaction with thionylaniline (69) and boron trifluoride. The mechanism proposed for this remarkable transformation involves reaiTangement of the adduct (70) derived from thionylaniline and the isobenzofuran, to the tricyclic intermediate (71). This presumably collapses to the S-sultam (72), which yields the isoindole (65) upon extrusion of sulfur dioxide. Loss of sulfur dioxide, both from S-sultones and unsaturated S-sultams, is well documented. ... 

A -p-Bromobenzylidene-A-methylhydrazino)-6-chloroquinoxaline from its 4-oxide (270) [Me02CC=CC02Me, Me2NCHO, reflux, 2 h 30% this is a one-pot version involving cyclization to a tricyclic intermediate (see Section 4.6.2.3) and its subsequent degradation (see Section 1.7.14)]. ... 

Ring transposition processes are well established in six-membered heteroaromatic systems. Recent studies have centered on perfluoro systems in which bicyclic and tricyclic intermediates are sufficiently stable to permit isolation or at least detection. Thus, on irradiation in CF2C1CFC12, the perfluoropyridine 207 is converted into the azabicyclo[2.2.0]hexa-2,5-diene 208 and the two azaprismanes 209 and 210.154 An azabicyclo[2.2.0]hexa-2,5-diene has also been shown to be an intermediate in the photorearrangement of substituted 2-methylpyridines to o-substituted anilines.155 Diaza-bicyclo[2.2.0]hexa-2,5-dienes have similarly been shown to be intermediates in the conversion of fluorinated pyridazines (211) into the corresponding pyrazines (212)156 the proposed pathway is outlined in Scheme 7. Photoproducts which are formally dimers of intermediate azetes have been obtained when analogous reactions are carried out in a flow system.157... 

Reactions with dialdehydes allow the introduction of two additional rings in one step. Thus, condensation of 1 -(2-aminoethyl)pyrrole with glutaraldehyde and benzotriazole gives tricyclic intermediate 627 in which the benzotriazolyl moiety can be readily substituted with nucleophiles to give products 628 (Scheme 97) <2002JOC8220>. Condensation of ethyl ester of L-tryptophan with 2,5-dimethoxytetrahydrofuran and benzotriazole in acetic acid gives tetracyclic intermediate 629 which upon treatment with nucleophiles (silyl derivatives) is converted to products 630 <1999T3489>. 

Other applications of the [6 + 2]- and [6 + 4]-cycloaddition reactions in total synthesis have been reviewed.127 The two representative examples shown in Scheme 38 illustrate their use in the total synthesis of /3-cedrene and the taxane ABC ring system. The total synthesis of /3-cedrene utilized an intramolecular [6 + 2]-reaction128 to set up a tricyclic intermediate and the synthesis of the taxane ABC ring system is accomplished via a [6+ 4]-cycloaddition. 

The above intramolecular diene cyclizations are likely to proceed through a similar set of reactions as shown in Scheme 6.2 for the intermolecular variants. Thus, as depicted in Scheme 6.6, formation of the zirconacyclopropane at the less hindered terminal alkene (—> ii), generation of the tricyclic intermediate iii, Zr—Mg exchange through the intermediacy of zirconate iy and 3-H abstraction and Mg alkoxide elimination in v may lead to the formation of the observed product. Additional kinetic and mechanistic studies are required before a more detailed hypothesis can be put forward. 

An equilibrium mixture of the cyclohexane- 1,3-dione (42) and its enol form (43) was irradiated in the presence of cyclopentene in MeOH to afford the intermediate (44), which was readily transformed to the tricyclic intermediate (45) and subsequently followed an retroaldolization sequence to give the cyclooctanedione (46) in 90 % yield. When refluxed with titanium trichloride and K metal in THF for 5 min., compound (46) gave the diol (47) 21K... 

Transformation of the thiadiazolopyrimidine compound 138 to the fused dithiazole 140 also follows a fairly complicated pathway <2004JHC99>. When the derivative 138 is treated with carbon disulfide, a cyclization reminiscent of 1,3-dipolar cyclization takes place with the reagent acting as a dipolarophile to give a />OT-fused tricyclic intermediate containing a hypervalent sulfur atom 139. This intermediate can undergo isothiocyanate elimination to furnish 140. It is interesting to note that the sulfur atom of the thione moiety in the product is derived from carbon disulfide. 

Pursuing the synthesis of angelmicin B, Mootoo prepared the tricyclic intermediate fragment 93 from D-xylose derivative 90 (Fig. 31).46... 

Catalytic hydrogenation of the triple bond (Pd/C) and oxidation of the acetal in acid medium led to lactone 13. which could be cyclised directly to the tricyclic intermediate 5. according to a Dieckmann condensation induced by sodium methylsulphinylmethylide in DMSO. The cyclisation takes place through intermediate 14. Compound 5 was a diastereomeric mixture still, but on treatment with aqueous alkali, at room temperature, gave a crystalline compound in about 30-35% yield, to which the cis-anti-cis- configuration was assigned (in fact an equilibration through the intermediate A may take place). 

The mechanism of this conversion was formulated to occur by an initial addition of the ammonia at position 2 and of the anion of the keto compound (or the enamine) at position 6, i.e., formation of 124. It is of course possible that this addition pattern can be reversed addition of the ammonia at position 6 and of the anion at position 2. In both addition products an internal cyclization occurs by attack of the nitrogen of the amino group on the keto function, yielding the tricyclic intermediate 125. Aromatization occurs by loss of A-methyl-a-nitroacetamide (Scheme III.62). 

Chebanov et al. in [59] offered the key stages of all these three MCRs. According to their hypothesis at room temperature under ultrasonication, the reaction passed via kinetically controlled intermediate 56 with the formation of quinazolinones 54 (Scheme 25). The high-temperature protocol allowed the reaction following via thermodynamically preferable tricyclic intermediate 57. 

The mechanism of the formation of tricyclic intermediates 56 and 57 is also the important and conflicting matter. For example, Quiroga et al. [83] showed that these MCRs, the most probable, proceed via preliminary Knoevenagel condensation and Michael addition (Scheme 26). At the same time they rejected another pathway including the generation of enamine 60, because no reaction was observed between it and aromatic aldehyde when their mixture was refluxed in ethanol. 

Scheme 26 Possible mechanism of tricyclic intermediate formation...

Iprindol (25) is yet another antidepressant drug that differs structurally from the classical tricyclic antidepressants. Condensation of phenylhydrazine and cyclooctanone by the Rogers-Corson modification of the Fischer indole synthesis affords the tricyclic intermediate, 24. The active hydrogen of 6,7,8,9,10-hexahydro-5H-cyclooct[b]indole (24) is removed by reaction with sodium metal in DMF and the resulting salt condensed with 3-dimethylaminopropyl chloride. There is thus obtained iprindol (25). ... 

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